title: Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial.
abstract: OBJECTIVE
  To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434).
  
  
  METHODS
  ART-naive adults with CD4 cell count of 200 cells/μl or less, newly diagnosed tuberculosis, and at least one follow-up visit after ART initiation were included in this analysis. Each case of suspected TB-IRIS was systematically validated by two physicians not involved in patients' management. Factors associated with occurrence of TB-IRIS were identified using the Cox proportional hazard model.
  
  
  RESULTS
  Among 597 patients, 26% experienced TB-IRIS with an incidence rate of 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4-44.4]. Main clinical manifestations included new or worsening lymphadenopathy (77.4%) and fever (68.4%). Chest radiograph revealed new or worsening abnormalities in 53.4%. Symptoms resolved in 95.5% of patients. Six deaths were directly related to TB-IRIS. Initiating ART early increased the risk of TB-IRIS by 2.61 (95% CI 1.84-3.70). Extrapulmonary or disseminated tuberculosis, CD4 cell count of 100 cells/μl or less, and HIV RNA concentration more than 6 log10 copies/ml were also significantly associated with higher risk of TB-IRIS.
  
  
  CONCLUSIONS
  Shortening the delay between tuberculosis treatment onset and ART initiation to 2 weeks was associated with an increased risk of developing TB-IRIS. However, TB-IRIS was generally easily manageable. Given the marked reported survival advantage of early ART initiation after tuberculosis treatment onset, these data indicate that fear of TB-IRIS should not be an impediment to early ART in adults with advanced immunodeficiency in resource-limited, high burden settings.
authors.affiliation: aFrench National Agency for Research on AIDS and Viral Hepatitis (ANRS), Ho Chi Minh City, Vietnam bInstitut Pasteur du Cambodge, Phnom Penh, Cambodia cCambodian Health Committee, Phnom Penh, Cambodia dInstitut Pasteur, Paris, France eCalmette Hospital, Phnom Penh, Cambodia fKhmer Soviet Friendship Hospital, Phnom Penh, Cambodia gDonkeo Provincial Hospital, Takeo, Cambodia hMédecins Sans Frontières, Phnom Penh, Cambodia iSiem Reap Referral Hospital, Siem Reap, Cambodia jAssistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Le Kremlin-Bicêtre, France kProgram in Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Laureillard
authors.forename: Olivier
authors.initials: O
authors.lastname: Marcy
authors.forename: Yoann
authors.initials: Y
authors.lastname: Madec
authors.forename: Sokeo
authors.initials: S
authors.lastname: Chea
authors.forename: Sarin
authors.initials: S
authors.lastname: Chan
authors.forename: Laurence
authors.initials: L
authors.lastname: Borand
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernandez
authors.forename: Narom
authors.initials: N
authors.lastname: Prak
authors.forename: Chindamony
authors.initials: C
authors.lastname: Kim
authors.forename: Bunnet
authors.initials: B
authors.lastname: Dim
authors.forename: Eric
authors.initials: E
authors.lastname: Nerrienet
authors.forename: Thim
authors.initials: T
authors.lastname: Sok
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Delfraissy
authors.forename: Anne E
authors.initials: AE
authors.lastname: Goldfeld
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Blanc
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002160:Cambodia; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D008297:Male; D018570:Risk Assessment; D014376:Tuberculosis / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000995:Antitubercular Agents